Neurodegenerative disease refers to a class of diseases caused by progressive pathological changes of nervous system, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), etc. Since the cause for the development of this class of diseases is complex, and the pathogenic mechanism is not clear yet, there is no effective therapeutic agent yet.
FK506 binding proteins (FKBPs), named for the capability of binding to immunosuppressant FK506 (tacrolimus), are important mediators for FK506 to exert immunosuppressive action, and their physiological function has not been completely identified yet. Steiner J. P. et al. found in 1992 that the concentration of FKBPs in brain and periphery was much greater than that in immunologic tissues, and it was thus conjectured that there might be a certain relationship between FKBPs and nervous system. The results obtained by Dawson et al. show that FK506 can block nerve excitotoxicity caused by activation of NMDA receptor (N-methyl-D-aspartic acid receptor) by glutamic acid. It is supposed that this might be because after the inhibition of Calcineurin by FKBPs, the phosphorylation level of nitric oxide synthetase (NOS) increases, which inhibits the catalytic activity of NOS, thereby avoiding the injury of neurons by NO. In addition, it is found by studies that a protein closely associated with the growth of neurons—GAP43 (growth associated protein-43) is also a substrate for Calcinerin, the nerve regeneration of injured facial nerve and sciatic nerve is always accompanied by a significant increase in the mRNA level of GAP43, and meanwhile the mRNA level of FKBPs also increases correspondingly. These findings show that FKBPs may be associated with nerve growth. People are inspired by the above results and finally find organic small-molecule compounds capable of promoting nerve growth, from FKBPs ligands, and therefore FKBPs are also known as neuroimmunophilins.
Based on such an inventive concept, in 1994, Lyons et al. found by studies that immunosuppressive agent FK506 had a significant activity of promoting nerve growth in vitro, and set a precedent for research on small-molecule nerve growth promoters. Although the mechanism underlying the nerve growth promotion and protection of FKBP family ligands has not been identified completely yet, more and more studies show that FKBPs are involved in the mediation of the process. By evaluation using in vitro assays (such as chick embryonic dorsal root ganglion growth assay, PC 12 cell differentiation assay and assay on oxidative damage of nerve cell lines) and multiple animal models (such as rat peripheral sciatic nerve transected model, diabetes mellitus mouse model of peripheral neurodegenerative disease, animal model of Parkinson's disease and presenile dementia animal model), the results show that some compounds, which were designed based on FKBPs structures and synthesized, had significantly nerve growth-promoting and protective function. The typical one among these compounds is GPI1485 from Guilford Pharmaceuticals Inc. The Company uses GPI1485 as a prophylactic and therapeutic drug for Parkinson's disease and apoplexy, its phase II clinical research has finished, and the phase III clinical research is ongoing. Meanwhile, a lot of highly active compounds emerges constantly, and therefore FKBPs have become an important target for drugs for preventing and treating neurodegenerative diseases.
The Chinese Invention Patent ZL01142744.2 (Substituted 6-membered N-heterocyclic compounds and their uses as neurological regulator) discloses a class of FKBP ligands with new structures capable of promoting nerve regeneration, among which Compound 4 is the optimal compound. However, it is found by studies that Compound 4 has low blood-brain barrier penetration, low melting point, and is in a state of oil at room temperature and therefore is not suitable for use in the manufacture of a medicament for preventing/treating a neurodegenerative disease. The Chinese Invention Patent CN102675244 discloses its optimized compounds, however, they can be further improved with respect to the activity of promoting the growth of nerve fibers and in vivo efficacy.